title: Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function.
abstract: Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity.
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45237, USA. barrerjg@mail.uc.edu
authors.forename: Jason G
authors.initials: JG
authors.lastname: Barrera
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Jones
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
authors.forename: David A
authors.initials: DA
authors.lastname: D'Alessio
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
mesh_terms: D050154:Adiposity / Q000187:drug effects / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D004041:Dietary Fats; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D005455:Fluorescent Antibody Technique; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006963:Hyperphagia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017403:In Situ Hybridization; D007276:Injections, Intraventricular; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology; D052336:Proglucagon / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques
chemical_list: D004041:Dietary Fats; D010446:Peptide Fragments; D012333:RNA, Messenger; C083773:exendin (9-39); D052336:Proglucagon; D052216:Glucagon-Like Peptide 1